Cannabis one of the most commonly used and abused illicit substances may produce harmful effects in some individuals. In laboratory studies, we have shown that Delta-9-tetrahydrocannabinol (d-9rTHC) induced transient but clinically significant psychotomimetic and amnestic effects in some but not all carefully screened healthy individuals. Epidemiological data suggest that cannabis is a modest risk for the emergence of psychosis and psychotic disorders. Further, a recent report suggests that polymorphisms of the gene for the enzyme catechol-O-methyltransferase (COMT) might moderate the risk of psychosis following cannabis exposure. COMT Val108/58Met polymorphism moderates executive function and the physiology of the prefrontal cortex in humans and is indirectly associated with increased mesolimbic dopamine transmission. Cannabinoids have been shown to increase dopaminergic transmission both in the prefrontal cortex and striatum, and these effects might contribute to the psychotomimetic and amnestic effects of cannabinoids. Similarly, hippocampal GABAergic systems may contribute to the psychotomimetic and amnestic effects of cannabinoids. Hypotheses: Polymorphisms of the genes for COMT and GABRA2 moderate the psychotomimetic and amnestic response to d-9-THC. Methods: 81 healthy subjects (27 each of val-val, val-met and met-met genotype) will complete 2 test days during which they will receive d-9-THC (placebo or 2.5 mg) intravenously over 20 minutes in randomized counterbalanced fashion under double-blind conditions. Primary outcomes include psychotomimetic effects (PANSS positive symptoms subscale) and total immediate recall and delayed free deficits (Rey Auditory Verbal Learning Test) will be measured. Secondary outcomes include measures of spatial working memory, delayed recognition memory and attention. Results: Pilot data (n=15) show that otherwise healthy individuals homozygous for 1) the COMT Val108/58Met allele (Val-Val) and 2) the "tt" genotype of a SNP marker (rs279858) of the GABRA2 gene, are more vulnerable to experience clinically significant psychotomimetic and amnestic effects induced by d-9-THC. [unreadable] [unreadable] [unreadable]